This invention relates to storage stable injectable pamidronate alkaline salt solutions. The invention also relates to the preparation and use of these solutions in non-reactive containers.
Pamidronate disodium, also known as disodium 3-amino-1-hydroxypropane-1,1-diphosphonate (I), is used in the treatment of diseases associated with calcium and/or 
phosphate metabolism. Schmidt-Dxc3xcnker, U.S. Pat. No. 3,962,432, disclosed that aminoalkane-diphosphonic acids or their water-soluble salts are suitable for the therapeutic treatment of disorders associated with abnormal deposition of calcium salts, including inflammatory diseases, arteriosclerosis and osteoporosis.
Novartis Pharmaceutical Corp. currently markets Aredia(copyright), a lyophilized pamidronate disodium pentahydrate, which is used to inhibit bone resorption and to treat hypercalcemia, as well as to treat metastatic bone pain. The Physicians Desk Reference 2000 reports that Aredia(copyright), when reconstituted with Sterile Water for Injection, is capable of being stored under refrigeration for up to 24 hours. Stahl et al., U.S. Pat. No. 4,711,880, disclosed a crystalline form of pamidronate disodium and a pharmaceutical preparation intended for enteral administration containing the crystalline salt.
This invention is directed towards a storage stable liquid pamidronate alkaline salt composition in a sealed storage vessel having an inner surface which is non-reactive with the pamidronate alkaline salt composition. The pamidronate alkaline salt may be, for example, pamidronate disodium or pamidronate dipotassium.
In one embodiment, the invention is directed to a packaged composition of a pamidronate alkaline salt in a sealed storage vessel. The pamidronate salt composition comprises a pamidronate alkaline salt, water, a sugar, a pharmaceutically acceptable base, and a pharmaceutically acceptable acid. The inner surface of the sealed storage vessel may be made of any material which is non-reactive with the pamidronate alkaline salt composition.
In another embodiment, the invention is directed to a method for preparing a packaged pamidronate alkaline salt composition by (a) combining a sugar with water; (b) combining the mixture of step (a) with pamidronic acid to form a pamidronic acid slurry; (c) adding to the pamidronic acid slurry sufficient aqueous solution of sodium hydroxide or potassium hydroxide to yield a solution having a pH of about 8.5; (d) adding to the resultant solution a pharmaceutically acceptable acid in an amount sufficient to lower the pH of the solution to about 6.5; (e) transferring the solution having a pH of about 6.5 into a vessel having an inner surface which does not react with the solution; and (f) sealing the vessel.
The present invention is based on the discovery that storage vessels made of glass may react with the pamidronate alkaline salt compositions. It is believed that glass may leach calcium or silicate which may react with pamidronate salt and thereby inhibit its therapeutic effectiveness. The present invention is directed to a storage stable liquid composition of a pamidronate alkaline salt in a sealed storage vessel having an inner surface which is non-reactive with the pamidronate salt composition. Thus, the inner surface of the storage vessel is made of a material other than glass.
In one embodiment, the invention is directed to a packaged composition of a pamidronate alkaline salt in a sealed storage vessel. The pamidronate salt composition comprises a pamidronate alkaline salt, water, a sugar, a pharmaceutically acceptable base, and a pharmaceutically acceptable acid. The inner surface of the sealed storage vessel may be made of any material which is non-reactive with the pamidronate alkaline salt composition. The pamidronate alkaline salt may be, for example, pamidronate disodium or pamidronate dipotassium.
Typically, the sealed storage vessel is a vial. In one embodiment, the inner surface of the sealed storage vessel is made of plastic. For example, the inner surface of the sealed storage vessel may be made of polypropylene. Another type of non-glass vials, Resin CZ(copyright) vials, is available from West Pharmaceutical Services (Lionville, Pa.).
Sugars, which may be used in the pamidronate alkaline salt compositions of the present invention, include mannitol, lactose and sucrose. Typically, the sugar is mannitol.
Pharmaceutically acceptable bases, which may be used in the pamidronate alkaline salt compositions of the present invention, include sodium hydroxide and potassium hydroxide.
Pharmaceutically acceptable acids, which may be used in the pamidronate alkaline salt compositions of the present invention, include phosphoric acid, nitric acid, sulfuric acid, hydrochloric acid, methanesulphonic acid, benzenesulphonoic acid, acetic acid, citric acid, lactic acid, propionic acid, tartaric acid, glutamic acid, maleic acid, ascorbic acid, fumaric acid, succinic acid, methyl sulfuric acid, and benzyl sulfonic acid. Typically, the pharmaceutically acceptable acid is phosphoric acid.
The compositions of the present invention typically have a pH between about 6.0 and about 9.0. Most often, the composition has a pH of about 6.5.
In another embodiment, the invention is directed to a method for preparing a packaged liquid pamidronate alkaline salt composition by (a) combining a sugar with water; (b) combining the mixture of step (a) with pamidronic acid to form a pamidronic acid slurry; (c) adding to the pamidronic acid slurry sufficient aqueous solution of sodium hydroxide or potassium hydroxide to yield a solution having a pH of about 8.5; (d) adding to the resultant solution a pharmaceutically acceptable acid in an amount sufficient to lower the pH of the solution to about 6.5; (e) transferring the solution having a pH of about 6.5 into a vessel having an inner surface which does not react with the solution; and (f) sealing the vessel. Alternatively, a pamidronic acid aqueous slurry can be treated with aqueous sodium hydroxide or potassium hydroxide to form an aqueous solution of pamidronate disodium or pamidronate dipotassium. This solution can then be combined with mannitol and the resulting solution acidified to a pH of about 6.5 with, for example, phosphoric acid.
Sugars, which may be used in the method of this invention, include mannitol, lactose and sucrose. Typically, the sugar is mannitol.
Pharmaceutically acceptable acids, which may be used in the method of this invention, include phosphoric acid, nitric acid, sulfuric acid, hydrochloric acid, methanesulphonic acid, benzenesulphonoic acid, acetic acid, citric acid, lactic acid, propionic acid, tartaric acid, glutamic acid, maleic acid, ascorbic acid, fumaric acid, succinic acid, methyl sulfuric acid, and benzyl sulfonic acid. Typically, the pharmaceutically acceptable acid is phosphoric acid.
The inner surface of the storage vessel used in the method of the present invention may be made of any material which is non-reactive with the pamidronate alkaline salt composition of the invention. For example, the inner surface of the storage vessel may be made of plastic, such as polypropylene.
The pamidronate alkaline salt compositions of the present invention may be useful for treating diseases associated with calcium and/or phosphate metabolism in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may vary depending upon the type of administration desired, e.g., enteral, topical or parenteral.
In preparing the pharmaceutical compositions of the present invention in enteral liquid dosage forms (e.g., solutions), typical pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be employed. For parenteral administration, a carrier will typically comprise sterile water although other ingredients, that aid in solubility or serve as preservatives, may also be included.
The pharmaceutical compositions of the present invention are generally administered in the form of a daily dosage unit at concentrations from about 1 xcexcg/kg of body weight to about 500 mg/kg of body weight. Typically the compositions of the present invention are administered in a daily dosage of from about 10 xcexcg/kg to about 250 mg/kg. Most often the compositions of the present invention are administered in a daily dosage of from about 20 xcexcg/kg to about 100 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
Typically, pamidronate disodium is administered intravenously in dosages of 30 mg, 60 mg or 90 mg over an infusion period of either 4 or 24 hours.